Treatment of adipocytes

ABSTRACT

The present disclosure provides compositions comprising a lyn kinase activator and TRPM8 agonist, and to methods of: reducing blood glucose levels, weight gain, or fat depot levels; treating metabolic syndrome, Syndrome X, obesity, prediabetes, type II diabetes, type I diabetes; treating hypercholesterolemia, hypertension, coronary heart disease, diabetic neuropathy, lipodystrophy, diabetic retinopathy, erectile dysfunction, kidney disease, dyslipidemia, dyslipoproteinemia, a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, or pancreatitis; inducing the beiging of adipocytes; and preventing pancreatic beta cell degeneration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Application No. 62/483,584,filed Apr. 10, 2017, which is incorporated herein by reference in itsentirety.

FIELD

The present disclosure is directed, in part, to compositions comprisinga lyn kinase activator and a TRPM8 agonist, and to methods of: reducingblood glucose levels, weight gain, or fat depot levels; treatingmetabolic syndrome, Syndrome X, obesity, prediabetes, type II diabetes,type I diabetes; treating hypercholesterolemia, hypertension, coronaryheart disease, diabetic neuropathy, lipodystrophy, diabetic retinopathy,erectile dysfunction, kidney disease, dyslipidemia, dyslipoproteinemia,a peroxisome proliferator activated receptor-associated disorder,septicemia, a thrombotic disorder, or pancreatitis; inducing the beigingof adipocytes; and/or preventing pancreatic beta cell degeneration, byadministering a lyn kinase activator and a TRPM8 agonist.

BACKGROUND

Lyn kinase is a member of the src family of non-receptor proteintyrosine kinases that is predominantly expressed in B-lymphoid andmyeloid cells (see, Briggs et al., Biochemistry, 2000, 39, 489-495). Lynkinase participates in signal transduction from cell surface receptorsthat lack intrinsic tyrosine kinase activity. Activation of the lynkinase activity is necessary for proliferation of CD45+ myeloma cellsstimulated by IL-6 (see, Ishikawa et al, Blood, 2002, 99, 2172-2178).Association of lyn and fyn with the proline-rich domain of glycoproteinVI regulates intracellular signaling (see, Suzuki-Inoue et al., J. Biol.Chem., 2002, 277, 21561-21566). The lyn/CD22/SHP-1 pathway is alsoimportant in autoimmunity (see, Blasioli et al., Curr. Dir. Autoimmun.,2002, 5, 151-160).

Obesity, hyperlipidemia, and diabetes have been shown to play a causalrole in various disorders including, for example, atheroscleroticcardiovascular diseases, which currently account for a considerableproportion of morbidity in Western society. One human disorder, termed“Syndrome X” or “Metabolic Syndrome,” is manifested by defective glucosemetabolism (e.g., insulin resistance), elevated blood pressure (i.e.,hypertension), and a blood lipid imbalance (i.e., dyslipidemia) (see,Reaven, Annu. Rev. Med., 1993, 44, 121-131).

For many years, there was believed to be only two kinds of fat cells:white adipocytes, which come from fat precursors, have a primaryfunction to store fat and produce hormones; and brown adipocytes, whicharise from muscle precursors, are full of mitochondria to burn fat tocreate non-shivering thermogenic energy. The presence of brown adipocytetissue correlates with enhanced insulin sensitivity and energyexpenditure. In comparison to white adipocytes, brown adipocytes secretelevels of adiponectin and resistin that enhance whole body glucoseutilization. A third type of fat cell has been discovered: beigeadipocytes, which are essentially white adipocytes that have beeninduced into energy-burning cells similar to brown adipocytes. Onemethod of treating obesity may be to induce the creation of beigeadipocytes from white adipocytes. A hallmark of both brown and beigeadipocytes is the expression of thermogenic genes. However, while brownadipocytes express these genes at basal levels, beige adipocytes arethought to express them only in the presence of agonists such asadrenergic or naturetic peptides.

None of the currently commercially available drugs for modulating lynkinase or managing elevated glucose levels have a general utility inregulating lipid, lipoprotein, insulin and glucose levels in the blood.Thus, compounds that have one or more of these utilities are clearlyneeded. Furthermore, there is a clear need to develop safer drugs thatare efficacious at lowering serum cholesterol, increasing HDL serumlevels, preventing coronary heart disease, and/or treating existingdisease such as atherosclerosis, obesity, diabetes, and other diseasesthat are affected by glucose metabolism and/or elevated glucose levels.

SUMMARY

The present disclosure provides compositions comprising: a lyn kinaseactivator, or a pharmaceutically acceptable salt thereof, and atransient receptor potential cation channel subfamily M member 8 (TRPM8)agonist.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R¹ is an alkyl group; X is a halogen; Y is O, S, or NH; Z is Oor S; and n is an integer from 0 to 5 and m is 0 or 1, wherein m+n isless than or equal to 5; or a pharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R¹ is an alkyl group; X is a halogen; and n is an integer from0 to 5 and m is 0 or 1, wherein m+n is less than or equal to 5; or apharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein R¹ is an alkyl group and n is an integer from 0 to 5; or apharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein X is a halogen and in is an integer from 0 to 1; or apharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein: each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are, independently, ahydrogen, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, benzyl,cycloalkyl, halogen, heteroaryl, heterocycloalkyl, —CN, —OH, —NO₂, —CF₃,—CO₂H, —CO₂alkyl, or —NH₂; R₈ is an alkyl or hydrogen; X is O, S, NH, orN-akyl; and Z is O or S; or a pharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R¹ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R² is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1)OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R³ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R⁴ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R⁵ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); or two adjacent groups of R¹, R², R³, R⁴, and R⁵ canlink to form a fused cycloalkyl or fused heterocycloalkyl group, eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2)NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1); R is H,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1)S(O)NR^(c1)R^(d1),S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1); R^(a1), R^(b1), R^(c1), and R^(d1)are each, independently, selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from OH, NO₂,CN, amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,and C₁₋₆haloalkoxy; or R^(c1) and R^(d1) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, NO₂, CN,amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, andC₁₋₆haloalkoxy; R^(a2), R^(b2), R^(c2), and R^(d2) are each,independently, selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, NO₂, CN, amino,halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, andC₁₋₆haloalkoxy; or R^(c2) and R^(d2) together with the N atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup or heteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from OH, NO₂, CN, amino, halo,C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, andC₁₋₆haloalkoxy; Z¹ is O, S, or NR⁹; R⁹ is H, OH, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, aryloxy, heteroaryloxy, CN, or NO₂; Z²is O, S, or NR¹⁰; R¹⁰ is H, OH, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, aryloxy, heteroaryloxy, CN, or NO₂; L¹ is O, S, orNR¹¹; and R¹¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,C(O)R^(b1), C(O)NR^(c1)R^(d), C(O)OR^(a1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1); or apharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R², R³, and R⁴ are each, independently, H, halo, C₁₋₆alkyl,C₁₋₆hydroxyalkyl, or C₁₋₆haloalkyl; R⁷ is H, C₁₋₆alkyl, C(O)R^(b1),C(O)NR^(c1)R^(d), or C(O)OR^(a1); R⁸ is H, C₁₋₆alkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), or C(O)OR^(a1); R^(a1), R^(b1), R^(c1), and R^(d1)are each, independently, selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from OH, NO₂,CN, amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,and C₁₋₆haloalkoxy; or R^(c1) and R^(d1) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, NO₂, CN,amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, andC₁₋₆haloalkoxy; Z¹ is O or S; Z² is O or S; and L¹ is O or S; or apharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R², R³, R⁴, and R⁵ are each, independently, H, F, Cl, CH₃,SCH₃, OCH₃, C(CH₃)₃, CH(CH₃)₂, or C₂H₅; or a pharmaceutically acceptablesalt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R¹ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1)SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R² is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R³ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R⁴ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R⁵ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); or two adjacent groups of R¹, R², R³, R⁴, and R⁵ canlink to form a fused cycloalkyl or fused heterocycloalkyl group, eachoptionally substituted by 1, 2, or 3 substituents independently selectedfrom halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN,NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1) NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1); R^(a1), R^(b1), R^(c1), and R^(d1)are each, independently, selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from OH, NO₂,CN, amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,and C₁₋₆haloalkoxy; or R^(c1) and R^(d1) together with the N atom towhich they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group or heteroaryl group, each optionally substitutedwith 1, 2, or 3 substituents independently selected from OH, NO₂, CN,amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, andC₁₋₆haloalkoxy; R^(a2), R^(b2), R^(c2), and R^(d2) are each,independently, selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, and heterocycloalkylalkyl, wherein each of C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, NO₂, CN, amino,halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, andC₁₋₆haloalkoxy; or R^(c2) and R^(d2) together with the N atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup or heteroaryl group, each optionally substituted with 1, 2, or 3substituents independently selected from OH, NO₂, CN, amino, halo,C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, andC₁₋₆haloalkoxy; Z¹ is O, S, or NR⁹; R⁹ is H, OH, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, aryloxy, heteroaryloxy, CN, or NO₂; Z²is O, S, or NR¹⁰; R¹⁰ is H, OH, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, aryloxy, heteroaryloxy, CN, or NO₂; L¹ is O, S, orNR¹¹; R¹¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1); R¹⁰⁰ is a hydroxyl protecting group,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,C₃₋₆cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1), S(O)₂OR^(c1), P(O)OR^(f1)OR^(g1), orSi(R^(h1))₃, wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); R²⁰⁰ is a hydroxyl protecting group, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,C₃₋₆cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1) S(O)₂NR^(c1)R^(d1), S(O)₂OR^(c1), P(O)OR^(f1)OR^(g1), orSi(R^(h1))₃, wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4 or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2)OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2) NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); each R^(c1) is, independently, H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl; each R^(f1) is,independently, H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,C₂₋₆alkenyl, (C₁₋₆alkoxy)-C₁₋₆alkyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl,heteroarylalkyl, or heterocycloalkylalkyl; each R^(g1) is,independently, H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl; and each R^(h1) is, independently, H, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, cycloalkylalkyl,heterocycloalkylalkyl, arylalkyl, or heteroarylalkyl; or apharmaceutically acceptable salt thereof.

In some embodiments, the TRPM8 agonist is menthol, icilin, WS 3, or WS23. In some embodiments, the TRPM8 agonist is menthol.

The present disclosure also provides methods of reducing blood glucoselevels, weight gain, or fat depot levels in a mammal in need thereof,comprising administering to the mammal an effective amount of acomposition as described herein, or comprising administering a lynkinase activator and a TRPM8 agonist.

The present disclosure also provides methods of treating metabolicsyndrome, Syndrome X, obesity, prediabetes, type II diabetes, type Idiabetes in a mammal in need thereof, comprising administering to themammal an effective amount of a composition as described herein, orcomprising administering a lyn kinase activator and a TRPM8 agonist.

The present disclosure also provides methods of treatinghypercholesterolemia, hypertension, coronary heart disease, diabeticneuropathy, lipodystrophy, diabetic retinopathy, erectile dysfunction,kidney disease, dyslipidemia, dyslipoproteinemia, a peroxisomeproliferator activated receptor-associated disorder, septicemia, athrombotic disorder, or pancreatitis in a mammal in need thereof,comprising administering to the mammal an effective amount of acomposition as described herein, or comprising administering a lynkinase activator and a TRPM8 agonist.

The present disclosure also provides methods of inducing the beiging ofadipocytes in a mammal in need thereof, comprising administering to themammal an effective amount of a composition as described herein, orcomprising administering a lyn kinase activator and a TRPM8 agonist.

The present disclosure also provides methods of preventing pancreaticbeta cell degeneration, comprising administering to the mammal aneffective amount of a composition as described herein, or comprisingadministering a lyn kinase activator and a TRPM8 agonist.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the progressive reduction in fasting plasma glucose (FPG)upon treatment with Compound 102.

FIG. 2 shows continued weight loss 1 week after treatment with Compound102.

FIG. 3 shows human adipocytes treated with Compound 102 experiencedsignificant increases, at day 4, in the expression of several genesassociated with the beiging of white adipose tissue.

FIG. 4 shows continued to increase of beige adipose tissue GLUT4 rRNAand UCP1 mRNA over a 7-day treatment period in primary cultured humanadipocytes.

FIG. 5 shows continued expression of GLUT4 protein over a 7-daytreatment period in primary cultured human adipocytes (40×magnification).

FIG. 6 shows continued expression of UCP1 protein over a 7-day treatmentperiod in primary cultured human adipocytes (40× magnification).

FIG. 7 shows induction of UCP1 Activators, PPARα and PGC-1β, bytreatment with Compound 102.

FIG. 8 shows induced expression of TRPM8 menthol receptor mRNA bytreatment with Compound 102.

FIG. 9 shows the reduction of Compound 102-induced UCP1 levels by PI3Ki,PKAi, and TRPM8Ri.

FIG. 10 (panel a) shows densitometry quantitation for levels of UCP-1adipose tissue protein observed in db/db mice treated for 3 weeks withCompound 102 (100 mg/kg qd); FIG. 10 (panel b) shows a correspondingWestern blot.

FIG. 11 shows blocking of Compound 102-induction of UCP-1 with a TRPM8inhibitor.

FIG. 12 (panels a and b) shows that menthol by itself does not induce“beiging” effects but, rather, potentiates the induction of beiging byCompound 102 in cultured primary human adipocytes.

FIG. 13 shows that menthol by itself does effect insulin sensitizationor glycemic control in a rodent oral glucose tolerance test, whereasmenthol potentiates the the insulin sensitizing action of Compound 102in a rodent oral glucose tolerance test.

DESCRIPTION OF EMBODIMENTS

As used herein, the terms “a” or “an” means that “at least one” or “oneor more” unless the context clearly indicates otherwise.

As used herein, the term “about” means that the numerical value isapproximate and small variations would not significantly affect thepractice of the disclosed embodiments. Where a numerical limitation isused, unless indicated otherwise by the context, “about” means thenumerical value can vary by ±10% and remain within the scope of thedisclosed embodiments.

As used herein, the term “alkoxy” means a straight or branched —O-alkylgroup of 1 to 20 carbon atoms, including, but not limited to, methoxy,ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In someembodiments, the alkoxy chain is from 1 to 10 carbon atoms in length,from 1 to 8 carbon atoms in length, from 1 to 6 carbon atoms in length,from 1 to 4 carbon atoms in length, from 2 to 10 carbon atoms in length,from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length,or from 2 to 4 carbon atoms in length. An alkoxy group can beunsubstituted or substituted with one or two suitable substituents.

As used herein, the term “alkyl” means a saturated hydrocarbon groupwhich is straight-chained or branched. An alkyl group can contain from 1to 20, from 2 to 20, from 1 to 10, from 2 to 10, from 1 to 8, from 2 to8, from 1 to 6, from 2 to 6, from 1 to 4, from 2 to 4, from 1 to 3, or 2or 3 carbon atoms. Examples of alkyl groups include, but are not limitedto, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl),butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl (e.g., n-pentyl,isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl,octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl,2,2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, and thelike. An alkyl group can be unsubstituted or substituted with one or twosuitable substituents.

As used herein, the term “alkenyl” means a straight or branched alkylgroup having one or more double carbon-carbon bonds and 2-20 carbonatoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, vinyl, allyl, pentenyl,hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl and the like. In someembodiments, the alkenyl chain is from 2 to 10 carbon atoms in length,from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length,or from 2 to 4 carbon atoms in length. The double bond of an alkenylgroup can be unconjugated or conjugated to another unsaturated group. Analkenyl group can be unsubstituted or substituted with one or twosuitable substituents.

As used herein, the term “alkynyl” means a straight or branched alkylgroup having one or more triple carbon-carbon bonds and 2-20 carbonatoms, including, but not limited to, acetylene, 1-propylene,2-propylene, ethynyl, propynyl, butynyl, pentynyl, hexynyl,methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl, and the like. In some embodiments, the alkynyl chainis 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length,from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms inlength. The triple bond of an alkynyl group can be unconjugated orconjugated to another unsaturated group. An alkynyl group can beunsubstituted or substituted with one or two suitable substituents.

As used herein, the term “animal” includes, but is not limited to,humans and non-human vertebrates such as wild, domestic, and farmanimals.

As used herein, the term “aryl” means a monocyclic, bicyclic, orpolycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons.In some embodiments, aryl groups have from 6 to 20 carbon atoms or from6 to 10 carbon atoms. Examples of aryl groups include, but are notlimited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl,indenyl, tetrahydronaphthyl, tolyl, fluorenyl, azulenyl, naphthyl,5,6,7,8-tetrahydronaphthyl, and the like. An aryl group can beunsubstituted or substituted with one or two suitable substituents.

As used herein, the term “aryloxy” means an —O-aryl group, wherein arylis as defined herein. An aryloxy group can be unsubstituted orsubstituted with one or two suitable substituents. The aryl ring of anaryloxy group can be a monocyclic ring, wherein the ring comprises 6carbon atoms, referred to herein as “(C₆)aryloxy.”

As used herein, the term “benzyl” means —CH₂-phenyl.

As used herein, the term “carbocycle” means a 5- or 6-membered,saturated or unsaturated cyclic ring, optionally containing O, S, or Natoms as part of the ring. Examples of carbocycles include, but are notlimited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl, andany of the heterocycles recited herein.

As used herein, the term “carbonyl” group is a divalent group of theformula —C(O)—.

As used herein, the term “carrier” means a diluent, adjuvant, orexcipient with which a compound is administered. Pharmaceutical carrierscan be liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. The pharmaceutical carriers canalso be saline, gum acacia, gelatin, starch paste, talc, keratin,colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents can be used.

As used herein, the term, “compound” means all stereoisomers, tautomers,and isotopes of the compounds described herein.

As used herein, the terms “comprising” (and any form of comprising, suchas “comprise”, “comprises”, and “comprised”), “having” (and any form ofhaving, such as “have” and “has”), “including” (and any form ofincluding, such as “includes” and “include”), or “containing” (and anyform of containing, such as “contains” and “contain”), are inclusive oropen-ended and do not exclude additional, unrecited elements or methodsteps.

As used herein, the term “cycloalkyl” means non-aromatic cyclichydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups thatcontain up to 20 ring-forming carbon atoms. Cycloalkyl groups caninclude mono- or polycyclic ring systems such as fused ring systems,bridged ring systems, and spiro ring systems. In some embodiments,polycyclic ring systems include 2, 3, or 4 fused rings. A cycloalkylgroup can contain from 3 to 15, from 3 to 10, from 3 to 8, from 3 to 6,from 4 to 6, from 3 to 5, or 5 or 6 ring-forming carbon atoms.Ring-forming carbon atoms of a cycloalkyl group can be optionallysubstituted by oxo or sulfido. Examples of cycloalkyl groups include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl,norcarnyl, adamantyl, and the like. Also included in the definition ofcycloalkyl are moieties that have one or more aromatic rings fused(having a bond in common with) to the cycloalkyl ring, for example,benzo or thienyl derivatives of pentane, pentene, hexane, and the like(e.g., 2,3-dihydro-1H-indene-1-yl, or 1H-inden-2(3H)-one-1-yl). Acycloalkyl group can be unsubstituted or substituted by one or twosuitable substituents.

As used herein, the term “halogen” means fluorine, chlorine, bromine, oriodine. Correspondingly, the meaning of the terms “halo” and “Hal”encompass fluoro, chloro, bromo, and iodo.

As used herein, the term “heteroaryl” means an aromatic heterocyclehaving up to 20 ring-forming atoms (e.g., C) and having at least oneheteroatom ring member (ring-forming atom) such as sulfur, oxygen, ornitrogen. In some embodiments, the heteroaryl group has at least one ormore heteroatom ring-forming atoms, each of which are, independently,sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl grouphas from 3 to 20 ring-forming atoms, from 3 to 10 ring-forming atoms,from 3 to 6 ring-forming atoms, or from 3 to 5 ring-forming atoms. Insome embodiments, the heteroaryl group contains 2 to 14 carbon atoms,from 2 to 7 carbon atoms, 2 to 5 carbon atoms, or 5 or 6 carbon atoms.In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclicand polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Examples ofheteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl,thienyl, imidazolyl, thiazolyl, indolyl (such as indol-3-yl), pyrryl,oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl,indolinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl,pyrazolyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl,xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl,phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl, phenoxazinyl, pyrazyl, phienyl, groups, and thelike. Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole,5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole,1,3,4-oxadiazole, pyridine, and 2-aminopyridine. A heteroaryl group canbe unsubstituted or substituted with one or two suitable substituents.

As used herein, the term “heterocycle” or “heterocyclic ring” means a 5-to 7-membered mono- or bicyclic or 7- to 10-membered bicyclicheterocyclic ring system any ring of which may be saturated orunsaturated, and which consists of carbon atoms and from one to threeheteroatoms chosen from N, O and S, and wherein the N and S heteroatomsmay optionally be oxidized, and the N heteroatom may optionally bequaternized, and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring.Particularly useful are rings containing one oxygen or sulfur, one tothree nitrogen atoms, or one oxygen or sulfur combined with one or twonitrogen atoms. The heterocyclic ring may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.Examples of heterocyclic groups include, but are not limited to,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl,pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl,quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same asmorpholinyl.

As used herein, the term “heterocycloalkyl” means non-aromaticheterocycles having up to 20 ring-forming atoms including cyclizedalkyl, alkenyl, and alkynyl groups, where one or more of thering-forming carbon atoms is replaced by a heteroatom such as an O, N,or S atom. Hetercycloalkyl groups can be mono or polycyclic (e.g.,fused, bridged, or spiro systems). In some embodiments, theheterocycloalkyl group has from 1 to 20 carbon atoms, or from 3 to 20carbon atoms. In some embodiments, the heterocycloalkyl group contains 3to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6ring-forming atoms. In some embodiments, the heterocycloalkyl group has1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 triplebonds. Examples of heterocycloalkyl groups include, but are not limitedto, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole,benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl,oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl,imidazolidinyl, pyrrolidino, piperidino, morpholinyl, thiomorpholinyl,pyranyl, pyrrolidin-2-one-3-yl, and the like. In addition, ring-formingcarbon atoms and heteroatoms of a heterocycloalkyl group can beoptionally substituted by oxo or sulfido. For example, a ring-forming Satom can be substituted by 1 or 2 oxo (form a S(O) or S(O)₂). Foranother example, a ring-forming C atom can be substituted by oxo (formcarbonyl). Also included in the definition of heterocycloalkyl aremoieties that have one or more aromatic rings fused (having a bond incommon with) to the nonaromatic heterocyclic ring including, but notlimited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, andbenzo derivatives of heterocycles such as indolene, isoindolene,isoindolin-1-one-3-yl, 4,5,6,7-tetrahydrothieno [2,3-c]pyridine-5-yl,5,6-dihydrothieno [2,3-c]pyridin-7(4H)-one-5-yl, and3,4-dihydroisoquinolin-1(2H)-one-3yl groups. Ring-forming carbon atomsand heteroatoms of the heterocycloalkyl group can be optionallysubstituted by oxo or sulfido. A heterocycloalkyl group can beunsubstituted or substituted with one or two suitable substituents.

As used herein, the term “hydrocarbyl group” means a monovalent groupselected from (C₁-C₈)alkyl, (C₂-C₈)alkenyl, and (C₂-C₈)alkynyl,optionally substituted with one or two suitable substituents. In someembodiments, the hydrocarbon chain of a hydrocarbyl group is from 1 to 6carbon atoms in length, referred to herein as “(C₁-C₆)hydrocarbyl.”

As used herein, the term “individual” or “patient,” usedinterchangeably, means any animal, including mammals, such as mice,rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses,or primates, such as humans.

As used herein, the phrase “in need thereof” means that the animal ormammal has been identified as having a need for the particular method ortreatment. In some embodiments, the identification can be by any meansof diagnosis. In any of the methods and treatments described herein, theanimal or mammal can be in need thereof.

As used herein, the phrase “integer from 1 to 5” means 1, 2, 3, 4, or 5.

As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat,or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or ahuman. In some embodiments, the mammal is a human.

As used herein, the term “modulate” refers to a change in the expressionand/or activity of a protein. In an illustrative embodiment, “modulate”refers to increase or decrease the expression and/or activity of aprotein.

As used herein, the term “n-membered”, where n is an integer, typicallydescribes the number of ring-forming atoms in a moiety, where the numberof ring-forming atoms is n. For example, pyridine is an example of a6-membered heteroaryl ring and thiophene is an example of a 5-memberedheteroaryl ring.

As used herein, the phrase “optionally substituted” means thatsubstitution is optional and therefore includes both unsubstituted andsubstituted atoms and moieties. A “substituted” atom or moiety indicatesthat any hydrogen on the designated atom or moiety can be replaced witha selection from the indicated substituent groups, provided that thenormal valency of the designated atom or moiety is not exceeded, andthat the substitution results in a stable compound. For example, if amethyl group is optionally substituted, then 3 hydrogen atoms on thecarbon atom can be replaced with substituent groups.

As used herein, the phrase “pharmaceutically acceptable” means thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith tissues of humans and animals. In some embodiments,“pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopeia orother generally recognized pharmacopeia for use in animals, and moreparticularly in humans.

As used herein, the phrase “pharmaceutically acceptable salt(s),”includes, but is not limited to, salts of acidic or basic groups.Compounds that are basic in nature are capable of forming a wide varietyof salts with various inorganic and organic acids. Acids that may beused to prepare pharmaceutically acceptable acid addition salts of suchbasic compounds are those that form non-toxic acid addition salts, i.e.,salts containing pharmacologically acceptable anions including, but notlimited to, sulfuric, thiosulfuric, citric, maleic, acetic, oxalic,hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate,napsydisylate, tosylate, besylate, orthophoshate, trifluoroacetate, andpamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds that include an amino moiety may form pharmaceuticallyacceptable salts with various amino acids, in addition to the acidsmentioned above. Compounds that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.Examples of such salts include, but are not limited to, alkali metal oralkaline earth metal salts and, particularly, calcium, magnesium,ammonium, sodium, lithium, zinc, potassium, and iron salts. The presentinvention also includes quaternary ammonium salts of the compoundsdescribed herein, where the compounds have one or more tertiary aminemoiety.

As used herein, the term “phenyl” means —C₆H₅. A phenyl group can beunsubstituted or substituted with one, two, or three suitablesubstituents.

As used herein, the terms “prevention” or “preventing” mean a reductionof the risk of acquiring a particular disease, condition, or disorder.

As used herein, the phrase “suitable substituent” or “substituent” meansa group that does not nullify the synthetic or pharmaceutical utility ofthe compounds described herein or the intermediates useful for preparingthem. Examples of suitable substituents include, but are not limited to:C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₅-C₆aryl, C₁-C₆alkoxy,C₃-C₅heteroaryl, C₃-C₆cycloalkyl, C₅-C₆aryloxy, —CN, —OH, oxo, halo,haloalkyl, —NO₂, —CO₂H, —NH₂, —NH(C₁-C₅alkyl), —N(C₁-C₅alkyl)₂,—NH(C₆aryl), —N(C₅-C₆aryl)₂, —CHO, —CO(C₁-C₆alkyl), —CO((C₅-C₆)aryl),—CO₂((C₁-C₆)alkyl), and —CO₂((C₅-C₆)aryl). One of skill in art canreadily choose a suitable substituent based on the stability andpharmacological and synthetic activity of the compounds describedherein.

As used herein, the phrase “therapeutically effective amount” means theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician. The therapeutic effect is dependentupon the disorder being treated or the biological effect desired. Assuch, the therapeutic effect can be a decrease in the severity ofsymptoms associated with the disorder and/or inhibition (partial orcomplete) of progression of the disorder, or improved treatment,healing, prevention or elimination of a disorder, or side-effects, or atleast one adverse effect of a disorder is ameliorated or alleviated. Theamount needed to elicit the therapeutic response can be determined basedon the age, health, size and sex of the subject. Optimal amounts canalso be determined based on monitoring of the subject's response totreatment.

As used herein, the terms “treat,” “treated,” or “treating” meantherapeutic treatment measures wherein the object is to slow down(lessen) an undesired physiological condition, disorder or disease, orobtain beneficial or desired clinical results. Beneficial or desiredclinical results include, but are not limited to, alleviation ofsymptoms; diminishment of extent of condition, disorder or disease;stabilized (i.e., not worsening) state of condition, disorder ordisease; delay in onset or slowing of condition, disorder or diseaseprogression; amelioration of the condition, disorder or disease state orremission (whether partial or total), whether detectable orundetectable; an amelioration of at least one measurable physicalparameter, not necessarily discernible by the patient; or enhancement orimprovement of condition, disorder or disease. Treatment may includeeliciting a clinically significant response without excessive levels ofside effects. Treatment may also include prolonging survival as comparedto expected survival if not receiving treatment.

The compounds of the disclosure are identified herein by their chemicalstructure and/or chemical name. Where a compound is referred to by botha chemical structure and a chemical name, and that chemical structureand chemical name conflict, the chemical structure is determinative ofthe compound's identity.

At various places in the present specification, substituents ofcompounds may be disclosed in groups or in ranges. It is specificallyintended that the invention include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆alkyl” is specifically intended to individually disclosemethyl, ethyl, propyl, C₄alkyl, C₅alkyl, and C₆alkyl, linear and/orbranched.

For compounds in which a variable appears more than once, each variablecan be a different moiety selected from the Markush group defining thevariable. For example, where a structure is described having two Rgroups that are simultaneously present on the same compound, the two Rgroups can represent different moieties selected from the Markush groupsdefined for R. In another example, when an optionally multiplesubstituent is designated in the form, for example,

then it is understood that substituent R can occur “s” number of timeson the ring, and R can be a different moiety at each occurrence.Further, in the above example, where the variable T¹ is defined toinclude hydrogens, such as when T¹ is CH₂, NH, etc., any H can bereplaced with a substituent.

It is further appreciated that certain features of the disclosure, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the disclosure which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable sub-combination.

It is understood that the present disclosure encompasses the use, whereapplicable, of stereoisomers, diastereomers and optical stereoisomers ofthe compounds of the disclosure, as well as mixtures thereof.Additionally, it is understood that stereoisomers, diastereomers, andoptical stereoisomers of the compounds of the disclosure, and mixturesthereof, are within the scope of the disclosure. By way of non-limitingexample, the mixture may be a racemate or the mixture may compriseunequal proportions of one particular stereoisomer over the other.Additionally, the compounds can be provided as a substantially purestereoisomers, diastereomers and optical stereoisomers (such asepimers).

The compounds described herein may be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended to be included within the scope of thedisclosure unless otherwise indicated. Compounds that containasymmetrically substituted carbon atoms can be isolated in opticallyactive or racemic forms. Methods of preparation of optically activeforms from optically active starting materials are known in the art,such as by resolution of racemic mixtures or by stereoselectivesynthesis. Many geometric isomers of olefins, C═N double bonds, and thelike can also be present in the compounds described herein, and all suchstable isomers are contemplated in the present disclosure. Cis and transgeometric isomers of the compounds are also included within the scope ofthe disclosure and can be isolated as a mixture of isomers or asseparated isomeric forms. Where a compound capable of stereoisomerism orgeometric isomerism is designated in its structure or name withoutreference to specific R/S or cis/trans configurations, it is intendedthat all such isomers are contemplated.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art, including, for example, fractionalrecrystallizaion using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods include, but are not limited to,optically active acids, such as the D and L forms of tartaric acid,diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malicacid, lactic acid, and the various optically active camphorsulfonicacids such as β-camphorsulfonic acid. Other resolving agents suitablefor fractional crystallization methods include, but are not limited to,stereoisomerically pure forms of α-methylbenzylamine (e.g., S and Rforms, or diastereomerically pure forms), 2-phenylglycinol,norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine,1,2-diaminocyclohexane, and the like. Resolution of racemic mixtures canalso be carried out by elution on a column packed with an opticallyactive resolving agent (e.g., dinitrobenzoylphenylglycine). Suitableelution solvent compositions can be determined by one skilled in theart.

Compounds may also include tautomeric forms. Tautomeric forms resultfrom the swapping of a single bond with an adjacent double bond togetherwith the concomitant migration of a proton. Tautomeric forms includeprototropic tautomers which are isomeric protonation states having thesame empirical formula and total charge. Examples of prototropictautomers include, but are not limited to, ketone-enol pairs,amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs,enamine-imine pairs, and annular forms where a proton can occupy two ormore positions of a heterocyclic system including, but not limited to,1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds also include hydrates and solvates, as well as anhydrous andnon-solvated forms.

Compounds can also include all isotopes of atoms occurring in theintermediates or final compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. For example, isotopesof hydrogen include tritium and deuterium.

In some embodiments, the compounds, or pharmaceutically acceptable saltsthereof, are substantially isolated. Partial separation can include, forexample, a composition enriched in the compound of the disclosure.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compound of the disclosure, orpharmaceutically acceptable salt thereof. Methods for isolatingcompounds and their salts are routine in the art.

Although the disclosed compounds are suitable, other functional groupscan be incorporated into the compound with an expectation of similarresults. In particular, thioamides and thioesters are anticipated tohave very similar properties. The distance between aromatic rings canimpact the geometrical pattern of the compound and this distance can bealtered by incorporating aliphatic chains of varying length, which canbe optionally substituted or can comprise an amino acid, a dicarboxylicacid or a diamine. The distance between and the relative orientation ofmonomers within the compounds can also be altered by replacing the amidebond with a surrogate having additional atoms. Thus, replacing acarbonyl group with a dicarbonyl alters the distance between themonomers and the propensity of dicarbonyl unit to adopt an antiarrangement of the two carbonyl moiety and alter the periodicity of thecompound. Pyromellitic anhydride represents still another alternative tosimple amide linkages which can alter the conformation and physicalproperties of the compound. Modern methods of solid phase organicchemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide SynthesisA Practical Approach IRL Press Oxford 1989) now allow the synthesis ofhomodisperse compounds with molecular weights approaching 5,000 Daltons.Other substitution patterns are equally effective.

The compounds described herein also include derivatives referred to asprodrugs, which can be prepared by modifying functional groups presentin the compounds in such a way that the modifications are cleaved,either in routine manipulation or in vivo, to the parent compounds.Examples of prodrugs include compounds as described herein that containone or more molecular moieties appended to a hydroxyl, amino,sulfhydryl, or carboxyl group of the compound, and that whenadministered to a patient, cleaves in vivo to form the free hydroxyl,amino, sulfhydryl, or carboxyl group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compoundsdescribed herein. Preparation and use of prodrugs is discussed in T.Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,ed. Edward B. Roche, American Pharmaceutical Association and PergamonPress, 1987, both of which are incorporated herein by reference in theirentireties.

Compounds containing an amine function can also form N-oxides. Areference herein to a compound that contains an amine function alsoincludes the N-oxide. Where a compound contains several amine functions,one or more than one nitrogen atom can be oxidized to form an N-oxide.Examples of N-oxides include N-oxides of a tertiary amine or a nitrogenatom of a nitrogen-containing heterocycle. N-Oxides can be formed bytreatment of the corresponding amine with an oxidizing agent such ashydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid) (see,Advanced Organic Chemistry, by Jerry March, 4th Edition, WileyInterscience).

The present disclosure provides compositions comprising one or more lynkinase activators, or pharmaceutically acceptable salts thereof, and aTRPM8 agonist.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R¹ is an alkyl group; X is a halogen; Y is O, S, or NH; Z is Oor S; and n is an integer from 0 to 5 and m is 0 or 1, wherein m+n isless than or equal to 5; or a pharmaceutically acceptable salt thereof.

In some embodiments, the alkyl group is methyl and n is 1. In someembodiments, the halogen is chlorine and m is 1. In some embodiments, Yis O. In some embodiments, Z is O. In some embodiments, R¹ is methyl, Yis O, Z is O, n is 1, and m is 0. In some embodiments, R¹ is in the metaposition. In some embodiments, X is chlorine, Y is O, Z is O, n is 0,and m is 1. In some embodiments, X is in the meta position.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R¹ is an alkyl group; X is a halogen; and n is an integer from0 to 5 and m is 0 or 1, wherein m+n is less than or equal to 5; or apharmaceutically acceptable salt thereof.

In some embodiments, the alkyl group is methyl and n is 1. In someembodiments, the halogen is chlorine and m is 1. In some embodiments, R¹is methyl, n is 1, and m is 0. In some embodiments, R¹ is in the metaposition. In some embodiments, X is chlorine, n is 0, and m is 1. Insome embodiments, X is in the meta position.

In some embodiments, the lyn kinase activator is of the formula:

wherein R¹ is an alkyl group and n is an integer from 0 to 5; or apharmaceutically acceptable salt thereof.

In some embodiments, R¹ is methyl, n is 1. In some embodiments, R¹ is inthe meta position.

In some embodiments, the lyn kinase activator is of the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein X is a halogen and m is an integer from 0 to 1; or apharmaceutically acceptable salt thereof. In some embodiments, X ischloro and m is 1. In some embodiments, X is in the meta position.

In some embodiments, the lyn kinase activator is of the formula:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

or a pharmaceutically acceptable salt thereof

In some embodiments, the lyn kinase activator is of the formula:

wherein:

each of R₁, R₂, R₃, R₄, R₅, R₆, and R₇ are, independently, a hydrogen,alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, benzyl, cycloalkyl,halogen, heteroaryl, heterocycloalkyl, —CN, —OH, —NO₂, —CF₃, —CO₂H,—CO₂alkyl, or —NH₂;

R₈ is an alkyl or hydrogen;

X is O, S, NH, or N-akyl; and

Z is O or S;

or a pharmaceutically acceptable salt thereof.

In some embodiments, R₈ is alkyl. In some embodiments, R₈ is methyl. Insome embodiments, R₈ is hydrogen. In some embodiments, X is oxygen. Insome embodiments, Z is oxygen. In some embodiments, at least one ofR₂-R₆ is alkyl. In some embodiments, at least one of R₂-R₆ is methyl. Insome embodiments, at least one of R₂-R₆ is halogen. In some embodiments,at least one of R₂-R₆ is chloro. In some embodiments, at least one ofR₂-R₆ is —CN, —OH, —NO₂, —CF₃, —CO₂H, —NH₂, or alkoxy. In someembodiments, R₂ is alkyl, each of R₁ and R₃-R₈ is hydrogen, and X and Zare O. In some embodiments, R₂ is methyl. In some embodiments, R₂ is ahalogen, each of R₁ and R₃-R₈ is hydrogen, and X and Z are O. In someembodiments, R₂ is chloro. In some embodiments, R₃ is alkyl, each of R₁,R₂ and R₄-R₈ is hydrogen, and X and Z are O. In some embodiments, R₃ ismethyl. In some embodiments, R₃ is a halogen, each of R₁, R₂, and R₄-R₈is hydrogen, and X and Z are O. In some embodiments, R₃ is chloro. Insome embodiments, R₄ is alkyl, each of R₁-R₃ and R₅-R₈ is hydrogen, andX and Z are O. In some embodiments, R₄ is methyl. In some embodiments,R₄ is a halogen, each of R₁-R₃ and R₅-R₈ is hydrogen, and X and Z are O.In some embodiments, R₄ is chloro. In some embodiments, R₅ is —CF₃, eachof R₁-R₄ and R₆-R₈ is hydrogen, and X and Z are O. In some embodiments,R₅ is —NH₂, each of R₁-R₄ and R₆-R₈ is hydrogen, and X and Z are O. Insome embodiments, R₆ is —CF₃, each of R₁-R₅ and R₇-R₈ is hydrogen, and Xand Z are O. In some embodiments, R₆ is —NH₂, each of R₁-R₅ and R₇-R₈ ishydrogen, and X and Z are O.

In some embodiments, the lyn kinase activator is of the formula:

wherein:

R¹ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1) wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R² is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R³ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1) wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2)NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R⁴ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c2)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R⁵ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

or two adjacent groups of R¹, R², R³, R⁴, and R⁵ can link to form afused cycloalkyl or fused heterocycloalkyl group, each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2)OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2) NR^(c2)S(O)NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1);

R⁸ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1),

R^(a1), R^(b1), R^(c1), and R^(d1) are each, independently, selectedfrom H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, NO₂, CN, amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, NO₂, CN, amino, halo, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

R^(a2), R^(b2), R^(c2), and R^(d2) are each, independently, selectedfrom H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,NO₂, CN, amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, NO₂, CN, amino, halo, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

Z¹ is O, S, or NR⁹;

R⁹ is H, OH, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, aryloxy,heteroaryloxy, CN, or NO₂;

Z² is O, S, or NR¹⁰;

R¹⁰ is H, OH, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, aryloxy,heteroaryloxy, CN, or NO₂;

L¹ is O, S, or NR¹¹; and

R¹¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1);

or a pharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein:

R², R³, and R⁴ are each, independently, H, halo, C₁₋₆alkyl,C₁₋₆hydroxyalkyl, or C₁₋₆haloalkyl;

R⁷ is H, C₁₋₆alkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1), or C(O)OR^(a1);

R⁸ is H, C₁₋₆alkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1), or C(O)OR^(a1);

R^(a1), R^(b1), R^(c1), and R^(d1) are each, independently, selectedfrom H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, NO₂, CN, amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, NO₂, CN, amino, halo, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

Z¹ is O or S;

Z² is O or S; and

L¹ is O or S;

or a pharmaceutically acceptable salt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein: R², R³, R⁴, and R⁵ are each, independently, H, F, Cl, CH₃,SCH₃, OCH₃, C(CH₃)₃, CH(CH₃)₂, or C₂H₅; or a pharmaceutically acceptablesalt thereof.

In some embodiments, the lyn kinase activator is of the formula:

wherein:

R¹ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R² is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R³ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R⁴ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R⁵ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1), wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

or two adjacent groups of R¹, R², R³, R⁴, and R⁵ can link to form afused cycloalkyl or fused heterocycloalkyl group, each optionallysubstituted by 1, 2, or 3 substituents independently selected from halo,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R⁶ is H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a1),SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1)OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c2)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), NR^(c1)S(O)₂R^(b1), orS(O)₂NR^(c2)R^(d2); wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl,is optionally substituted by 1, 2, 3, 4, or 5 substituents independentlyselected from halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2)OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)NR^(c2)R^(d2),NR^(c2)C(O)OR^(a2) NR^(c2)S(O)NR^(c2)R^(d2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R⁷ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), S(O)R^(b1)S(O)NR^(c1)R^(d1), S(O)₂R^(b1), orS(O)₂NR^(c1)R^(d1);

R^(a1), R^(b1), R^(c1), and R^(d1) are each, independently, selectedfrom H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, NO₂, CN, amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

or R^(c1) and R^(d1) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, NO₂, CN, amino, halo, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

R^(a2), R^(b2), R^(c2), and R^(d2) are each, independently, selectedfrom H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, and heterocycloalkylalkyl, whereineach of C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,NO₂, CN, amino, halo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

or R^(c2) and R^(d2) together with the N atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group or heteroarylgroup, each optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, NO₂, CN, amino, halo, C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, and C₁₋₆haloalkoxy;

Z¹ is O, S, or NR⁹;

R⁹ is H, OH, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, aryloxy,heteroaryloxy, CN, or NO₂;

Z² is O, S, or NR¹⁰;

R¹⁰ is H, OH, C₁₋₆alkoxy, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, aryloxy,heteroaryloxy, CN, or NO₂;

L¹ is O, S, or NR¹¹;

R¹¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1),S(O)₂R^(b1), or S(O)₂NR^(c1)R^(d1);

R¹⁰⁰ is a hydroxyl protecting group, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1), S(O)₂OR^(b1), P(O)OR^(f1)OR^(g1), or Si(R^(h1))₃,wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl, is optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

R²⁰⁰ is a hydroxyl protecting group, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl,heterocycloalkyl, aryl, heteroaryl, C(O)R^(b1), C(O)NR^(c1)R^(d1),C(O)OR^(a1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),S(O)₂NR^(c1)R^(d1), S(O)₂OR^(e1), P(O)OR^(f1)OR^(g1), or Si(R^(h1))₃,wherein each of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, and heteroaryl, is optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromhalo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₃₋₆cycloalkyl, aryl, heteroaryl, CN, NO₂, OR^(a2),SRa², C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)NR^(c2)R^(d2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), NR^(c2)S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2);

each R^(e1) is, independently, H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylalkyl, or heteroarylalkyl;

each R^(f1) is, independently, H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, (C₁₋₆alkoxy)-C₁₋₆alkyl, C₂₋₆alkynyl,aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocycloalkylalkyl;

each R^(g1) is, independently, H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl; and

each R^(h1) is, independently, H, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl,arylalkyl, or heteroarylalkyl; or a pharmaceutically acceptable saltthereof.

In some embodiments, the lyn kinase activator is a compound of theformula:

which is also known as 5-(m-tolyloxy)pyrimidine-2,4(1H,3H)-dione.

In some embodiments, the TRPM8 agonist is menthol, icilin, WS 3, or WS23. In some embodiments, the TRPM8 agonist is menthol. Icilin (CAS36945-98-9) is also known as3-(2-hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one,and has the formula:

WS 3 (CAS 39711-79-0) is also known asN-ethyl-2-isopropyl-5-methylcyclo-hexanecarboxamide, and has theformula:

WS 23 (CAS 51115-67-4) is also known asN,2,3-trimethyl-2-propan-2-ylbutanamide, and has the formula:

In some embodiments, more than one TRPM8 agonist can be used with one ormore lyn kinase activators.

In some embodiments, the composition comprises Compound 102 and menthol.In some embodiments, no other active ingredient is present in thecomposition.

In some embodiments, the compositions described herein arepharmaceutical compositions and comprise a pharmaceutically acceptablecarrier, vehicle, diluent, or excipient.

It will be understood that the compounds are illustrative only and notintended to limit the scope of the claims to only those compounds.

The compounds described herein can be synthesized by standard organicchemistry techniques known to those of ordinary skill in the art, forexample as described in U.S. Pat. Nos. 3,922,345 and 4,080,454, each ofwhich is incorporated herein by reference in its entirety.

Preparation of the compounds described herein can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety. Suitable hydroxyl protecting groups include, but are notlimited to, tert-butyldimethylsilyl (TBS), methoxymethyl ether (MOM),tetrahydropyranyl ether (THP), t-Butyl ether, allyl ether, benzyl ether,t-Butyldimethylsilyl ether (TBDMS), t-Butyldiphenylsilyl ether (TBDPS),acetic acid ester, and the like.

The compositions described herein contain a therapeutically effectiveamount of one or more of the lyn kinase activators and one or more TRPM8agonists, such as menthol, together with a suitable amount of apharmaceutically acceptable vehicle to provide the desired form foradministration to the patient.

Vehicles include, but are not limited to a diluent, adjuvant, excipient,or carrier with which a compound is administered. Such pharmaceuticalvehicles can be liquids, such as water and oils, including those ofpetroleum, animal, vegetable or synthetic origin, such as peanut oil,soybean oil, mineral oil, sesame oil and the like. The pharmaceuticalvehicles can be saline, gum acacia, gelatin, starch paste, talc,keratin, colloidal silica, urea, and the like. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.When administered to a patient, the compounds and pharmaceuticallyacceptable vehicles are preferably sterile. Water is a suitable vehiclewhen the compound is administered intravenously. Saline solutions andaqueous dextrose and glycerol solutions can also be employed as liquidvehicles, particularly for injectable solutions. Suitable pharmaceuticalvehicles also include excipients such as starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. The presentcompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In some embodiments, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in Remington's PharmaceuticalSciences, A. R. Gennaro (Editor) Mack Publishing Co.

The compounds can be contained in such formulations withpharmaceutically acceptable diluents, fillers, disintegrants, binders,lubricants, surfactants, hydrophobic vehicles, water soluble vehicles,emulsifiers, buffers, humectants, moisturizers, solubilizers,preservatives and the like. The pharmaceutical compositions can alsocomprise suitable solid or gel phase carriers or excipients. Examples ofsuch carriers or excipients include, but are not limited to, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols. In someembodiments, the compounds described herein can be used with agentsincluding, but not limited to, topical analgesics (e.g., lidocaine),barrier devices (e.g., GelClair), or rinses (e.g., Caphosol).

Suitable compositions include, but are not limited to, oral non-absorbedcompositions. Suitable compositions also include, but are not limited tosaline, water, cyclodextrin solutions, and buffered solutions of pH 3-9.

The compounds described herein, or pharmaceutically acceptable saltsthereof, can be formulated with numerous excipients including, but notlimited to, purified water, propylene glycol, PEG 400, glycerin, DMA,ethanol, benzyl alcohol, citric acid/sodium citrate (pH3), citricacid/sodium citrate (pH5), tris(hydroxymethyl)amino methane HCl (pH7.0),0.9% saline, and 1.2% saline, and any combination thereof. In someembodiments, excipient is chosen from propylene glycol, purified water,and glycerin.

In some embodiments, the formulation can be lyophilized to a solid andreconstituted with, for example, water prior to use.

When administered to a human, the compounds can be sterile. Water is asuitable carrier when the compound is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Suitable pharmaceutical carriers also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present compositions, if desired, can also contain minoramounts of wetting or emulsifying agents, or pH buffering agents.

In some embodiments, the compounds are formulated in accordance withroutine procedures as a pharmaceutical composition adapted foradministration to humans. Typically, compounds are solutions in sterileisotonic aqueous buffer. Where necessary, the compositions can alsoinclude a solubilizing agent. Compositions for intravenousadministration may optionally include a local anesthetic such aslidocaine to ease pain at the site of the injection. Generally, theingredients are supplied either separately or mixed together in unitdosage form, for example, as a dry lyophilized powder or water freeconcentrate in a hermetically sealed container such as an ampoule orsachette indicating the quantity of active agent. Where the compound isto be administered by infusion, it can be dispensed, for example, withan infusion bottle containing sterile pharmaceutical grade water orsaline. Where the compound is administered by injection, an ampoule ofsterile water for injection or saline can be provided so that theingredients may be mixed prior to administration.

The pharmaceutical compositions can be in unit dosage form. In suchform, the composition can be divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparations, for example, packeted tablets, capsules, and powdersin vials or ampules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

In some embodiments, a composition can be in the form of a liquidwherein the active agent (i.e., one of the facially amphiphilic polymersor oligomers disclosed herein) is present in solution, in suspension, asan emulsion, or as a solution/suspension. In some embodiments, theliquid composition is in the form of a gel. In other embodiments, theliquid composition is aqueous. In other embodiments, the composition isin the form of an ointment.

Suitable preservatives include, but are not limited to,mercury-containing substances such as phenylmercuric salts (e.g.,phenylmercuric acetate, borate and nitrate) and thimerosal; stabilizedchlorine dioxide; quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride;imidazolidinyl urea; parabens such as methylparaben, ethylparaben,propylparaben and butylparaben, and salts thereof; phenoxyethanol;chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol;phenylethyl alcohol; disodium EDTA; and sorbic acid and salts thereof.

Optionally one or more stabilizers can be included in the compositionsto enhance chemical stability where required. Suitable stabilizersinclude, but are not limited to, chelating agents or complexing agents,such as, for example, the calcium complexing agent ethylene diaminetetraacetic acid (EDTA). For example, an appropriate amount of EDTA or asalt thereof, e.g., the disodium salt, can be included in thecomposition to complex excess calcium ions and prevent gel formationduring storage. EDTA or a salt thereof can suitably be included in anamount of about 0.01% to about 0.5%. In those embodiments containing apreservative other than EDTA, the EDTA or a salt thereof, moreparticularly disodium EDTA, can be present in an amount of about 0.025%to about 0.1% by weight.

One or more antioxidants can also be included in the compositions.Suitable antioxidants include, but are not limited to, ascorbic acid,sodium metabisulfite, sodium bisulfite, acetylcysteine,polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol,methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium,sorbic acid, or other agents know to those of skill in the art. Suchpreservatives are typically employed at a level of from about 0.001% toabout 1.0% by weight.

In some embodiments, the compounds are solubilized at least in part byan acceptable solubilizing agent. Certain acceptable nonionicsurfactants, for example polysorbate 80, can be useful as solubilizingagents, as can acceptable glycols, polyglycols, e.g., polyethyleneglycol 400 (PEG-400), and glycol ethers.

Suitable solubilizing agents for solution and solution/suspensioncompositions are cyclodextrins. Suitable cyclodextrins includeα-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, alkylcyclodextrins(e.g., methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, anddiethyl-β-cyclodextrin), hydroxyalkylcyclodextrins (e.g.,hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin),carboxy-alkylcyclodextrins (e.g., carboxymethyl-β-cyclodextrin),sulfoalkylether cyclodextrins (e.g., sulfobutylether-β-cyclodextrin),and the like. Applications of cyclodextrins have been reviewed inRajewski et al., J. Pharm. Sciences, 1996, 85, 1155-1159. An acceptablecyclodextrin can optionally be present in a composition at aconcentration from about 1 to about 200 mg/ml, from about 5 to about 100mg/ml, or from about 10 to about 50 mg/ml.

In some embodiments, the composition optionally contains a suspendingagent. For example, in those embodiments in which the composition is anaqueous suspension or solution/suspension, the composition can containone or more polymers as suspending agents. Useful polymers include, butare not limited to, water-soluble polymers such as cellulosic polymers,for example, hydroxypropyl methylcellulose, and water-insoluble polymerssuch as cross-linked carboxyl-containing polymers. However, in someembodiments, compositions do not contain substantial amounts of solidparticulate matter, whether of the anti-microbial polymer or oligomeractive agent, an excipient, or both, as solid particulate matter, ifpresent, can cause discomfort and/or irritation of a treated eye.

One or more acceptable pH adjusting agents and/or buffering agents canbe included in the compositions, including acids such as acetic, boric,citric, lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, sodium lactate and tris-hydroxymethylaminomethane; and bufferssuch as citrate/dextrose, sodium bicarbonate and ammonium chloride. Suchacids, bases and buffers are included in an amount required to maintainpH of the composition in an acceptable range.

Optionally one or more acceptable surfactants, such as nonionicsurfactants, or co-solvents can be included in the compositions toenhance solubility of the components of the compositions or to impartphysical stability, or for other purposes. Suitable nonionic surfactantsinclude, but are not limited to, polyoxyethylene fatty acid glyceridesand vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil;and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol10, octoxynol 40; polysorbate 20, 60 and 80;polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic® F-68, F84and P-103); cyclodextrin; or other agents known to those of skill in theart. Typically, such co-solvents or surfactants are employed in thecompositions at a level of from about 0.01% to about 2% by weight.

One or more lubricating agents can also be included optionally in thecompositions to promote lacrimation or as a “dry eye” medication. Suchagents include, but are not limited to, polyvinyl alcohol,methylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone,and the like. It will be understood that promotion of lacrimation isbeneficial in the present invention only where lacrimation is naturallydeficient, to restore a normal degree of secretion of lacrimal fluid.Where excessive lacrimation occurs, residence time of the composition inthe eye can be reduced.

The compounds described herein can be formulated for parenteraladministration by injection, such as by bolus injection or continuousinfusion. The compounds can be administered by continuous infusionsubcutaneously over a period of about 15 minutes to about 24 hours.Formulations for injection can be presented in unit dosage form, such asin ampoules or in multi-dose containers, with an added preservative. Thecompositions can take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and can contain formulatory agents such assuspending, stabilizing and/or dispersing agents. In some embodiments,the injectable is in the form of short-acting, depot, or implant andpellet forms injected subcutaneously or intramuscularly. In someembodiments, the parenteral dosage form is the form of a solution,suspension, emulsion, or dry powder.

In some embodiments, the compounds are formulated in accordance withroutine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compounds forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the compositions may also include asolubilizing agent. Compositions for intravenous administration mayoptionally include a local anesthetic such as lidocaine to ease pain atthe site of the injection. Generally, the ingredients are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the compound is to be administered by infusion,it can be dispensed, for example, with an infusion bottle containingsterile pharmaceutical grade water or saline. Where the compound isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

The compounds described herein can also be formulated as a depotpreparation. Such long acting formulations can be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Depot injections can be administered at about 1to about 6 months or longer intervals. Thus, for example, the compoundscan be formulated with suitable polymeric or hydrophobic materials (forexample as an emulsion in an acceptable oil) or ion exchange resins, oras sparingly soluble derivatives, for example, as a sparingly solublesalt.

In some embodiments, the compositions can be administered orally.Compositions for oral delivery may be in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs, for example. Orally administered compositions maycontain one or more optionally agents, for example, sweetening agentssuch as fructose, aspartame or saccharin; flavoring agents such aspeppermint, oil of wintergreen, or cherry; coloring agents; andpreserving agents, to provide a pharmaceutically palatable preparation.Moreover, where in tablet or pill form, the compositions may be coatedto delay disintegration and absorption in the gastrointestinal tractthereby providing a sustained action over an extended period of time.Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds. Inthese later platforms, fluid from the environment surrounding thecapsule is imbibed by the driving compound, which swells to displace theagent or agent composition through an aperture. These delivery platformscan provide an essentially zero order delivery profile as opposed to thespiked profiles of immediate release formulations. A time delay materialsuch as glycerol monostearate or glycerol stearate may also be used.Oral compositions can include standard vehicles such as mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Such vehicles can be pharmaceutical grade.

For oral administration, the compounds described herein can beformulated by combining the compounds with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds to beformulated as tablets, pills, dragees, capsules, emulsions, liquids,gels, syrups, caches, pellets, powders, granules, slurries, lozenges,aqueous or oily suspensions, and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained by, for example, adding a solid excipient, optionally grindingthe resulting mixture, and processing the mixture of granules, afteradding suitable auxiliaries, if desired, to obtain tablets or drageecores. Suitable excipients include, but are not limited to, fillers suchas sugars, including, but not limited to, lactose, sucrose, mannitol,and sorbitol; cellulose preparations such as, but not limited to, maizestarch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and polyvinylpyrrolidone (PVP). If desired,disintegrating agents can be added, such as, but not limited to, thecross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof such as sodium alginate.

Orally administered compositions can contain one or more optionalagents, for example, sweetening agents such as fructose, aspartame orsaccharin; flavoring agents such as peppermint, oil of wintergreen, orcherry; coloring agents; and preserving agents, to provide apharmaceutically palatable preparation. Moreover, where in tablet orpill form, the compositions may be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compounds. Oral compositions can include standardvehicles such as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, etc. Such vehicles aresuitably of pharmaceutical grade.

Dragee cores can be provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include, but arenot limited to, push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol. The push-fit capsules can contain the active ingredients inadmixture with filler such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds can be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers can be added.

For buccal administration, the compositions can take the form of, suchas, tablets or lozenges formulated in a conventional manner.

In some embodiments, the compounds can be delivered in a controlledrelease system. In one embodiment, a pump may be used (see Langer,supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald etal., Surgery, 1980, 88, 507 Saudek et al., N. Engl. J. Med., 1989, 321,574). In another embodiment, polymeric materials can be used (seeMedical Applications of Controlled Release, Langer and Wise (eds.), CRCPres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, DrugProduct Design and Performance, Smolen and Ball (eds.), Wiley, New York(1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23,61; see, also Levy et al., Science, 1985, 228, 190; During et al., Ann.Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71, 105). Inyet another embodiment, a controlled-release system can be placed inproximity of the target of the compounds described herein, such as theliver, thus requiring only a fraction of the systemic dose (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115-138 (1984)). Other controlled-release systems discussed in thereview by Langer, Science, 1990, 249, 1527-1533) may be used.

In some embodiments, the compounds described herein can be delivered ina vesicle, in particular a liposome (see, Langer, Science, 1990, 249,1527-1533; Treat et al., in Liposomes in the Therapy of InfectiousDisease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York,pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generallyibid.).

For administration by inhalation, the compounds described herein can bedelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebulizer, with the use of a suitable propellant, such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit can be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as gelatin for use in an inhaler or insufflator can beformulated containing a powder mix of the compound and a suitable powderbase such as lactose or starch.

The compounds described herein can also be formulated in rectalcompositions such as suppositories or retention enemas, such ascontaining conventional suppository bases such as cocoa butter or otherglycerides. The compounds described herein can also be formulated invaginal compositions such as vaginal creams, suppositories, pessaries,vaginal rings, and intrauterine devices.

In transdermal administration, the compounds can be applied to aplaster, or can be applied by transdermal, therapeutic systems that areconsequently supplied to the organism. In some embodiments, thecompounds are present in creams, solutions, powders, fluid emulsions,fluid suspensions, semi-solids, ointments, pastes, gels, jellies, andfoams, or in patches containing any of the same.

The amount of a lyn kinase activator that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed in the compositions will also depend on theroute of administration, and the seriousness of the disease or disorder,and should be decided according to the judgment of the practitioner andeach patient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.001 milligram to 200 milligrams ofa compound per kilogram body weight. In some embodiments, the oral doseis about 0.01 milligram to about 70 milligrams per kilogram body weight,about 0.1 milligram to about 50 milligrams per kilogram body weight,about 0.5 milligram to about 20 milligrams per kilogram body weight,about 1 milligram to about 10 milligrams per kilogram body weight, orabout 5 milligrams of a compound per kilogram body weight. The dosageamounts described herein refer to total amounts administered; that is,if more than one compound is administered, the dosages correspond to thetotal amount of the compounds administered. Oral compositions cancontain 10% to 95% active ingredient by weight.

Suitable dosage ranges for intravenous (i.v.) administration are about0.01 milligram to about 100 milligrams per kilogram body weight, about0.1 milligram to about 35 milligrams per kilogram body weight, and about1 milligram to about 10 milligrams per kilogram body weight. Suitabledosage ranges for intranasal administration are generally about 0.01pg/kg body weight to about 1 mg/kg body weight. Suppositories generallycontain about 0.01 milligram to about 50 milligrams of a compound perkilogram body weight and comprise active ingredient in the range ofabout 0.5% to about 10% by weight. Recommended dosages for intradermal,intramuscular, intraperitoneal, subcutaneous, epidural, sublingual,intracerebral, intravaginal, transdermal administration oradministration by inhalation are in the range of about 0.001 milligramto about 200 milligrams per kilogram of body weight. Suitable doses ofthe compounds for topical administration are in the range of about 0.001milligram to about 1 milligram, depending on the area to which thecompound is administered. Effective doses may be extrapolated fromdose-response curves derived from in vitro or animal model test systems.Such animal models and systems are well known in the art.

The amount of TRPM8 agonist that will be effective in the treatment of aparticular disorder or condition disclosed herein will depend on thenature of the disorder or condition, and can be determined by standardclinical techniques. In addition, in vitro or in vivo assays mayoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed in the compositions will also depend on theroute of administration, and the seriousness of the disease or disorder,and should be decided according to the judgment of the practitioner andeach patient's circumstances. However, suitable dosage ranges foradministration of the TRPM8 agonist are generally from about 0.01 μM toabout 200 μM, from about 0.1 μM to about 150 μM, from about 1 μM toabout 100 μM, from about 5 μM to about 50 μM, from about 10 μM to about40 μM, from about 15 μM to about 35 μM, or from about 20 μM to about 30μM. In some embodiments, a suitable dosage for administration of theTRPM8 agonist is about 0.1 μM, about 1 μM, about 5 μM, about 10 μM,about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about40 μM, about 45 μM, about 50 μM, about 55 μM, about 60 μM, about 65 μM,about 70 μM, about 75 μM, about 80 μM, about 85 μM, about 90 μM, about95 μM, about 100 μM, about 105 μM, about 110 μM, about 115 μM, about 120μM, about 125 μM, about 130 μM, about 135 μM, about 140 μM, about 145μM, about 150 μM, about 155 μM, about 160 μM, about 165 μM, about 170μM, about 175 μM, about 180 μM, about 185 μM, about 190 μM, about 195μM, or about 200 μM.

The present disclosure also provides pharmaceutical packs or kitscomprising one or more containers filled with one or more compositions.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration. In some embodiments, the kit contains more than one lynkinase activator. In some embodiments, the kit contains more than oneTRPM8 agonist. In some embodiments, the kit comprises a lyn kinaseactivator and TRPM8 agonist in separate containers.

In some embodiments, the compositions can be used in combination therapywith at least one other therapeutic agent. The compound and theadditional therapeutic agent can act additively or synergistically. Insome embodiments, a composition described herein is administeredconcurrently with the administration of another therapeutic agent, whichcan be part of the same composition as the compound or a differentcomposition. In some embodiments, a composition described herein isadministered prior or subsequent to administration of anothertherapeutic agent. As many of the disorders for which the compositionsare useful in treating are chronic disorders, in some embodiments thecombination therapy involves alternating between administering acomposition described herein and a composition comprising anothertherapeutic agent, e.g., to minimize the toxicity associated with aparticular drug. The duration of administration of each drug ortherapeutic agent can be, e.g., one month, three months, six months, ora year. In some embodiments, when a composition described herein isadministered concurrently with another therapeutic agent thatpotentially produces adverse side effects, including but not limited to,toxicity, the therapeutic agent can advantageously be administered at adose that falls below the threshold at which the adverse side iselicited.

The present compositions can be administered together or separately,with a statin. Statins include but are not limited to atorvastatin,pravastatin, fluvastatin, lovastatin, simvastatin, and cerivastatin. Insome embodiments, the composition comprises a lyn kinase activator, aTRPM8 agonist, and a statin.

The present compositions can also be administered together, orseparately, with a PPAR agonist, for example a thiazolidinedione or afibrate. Thiazolidinediones include but are not limited to5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione,troglitazone, pioglitazone, ciglitazone, WAY-120,744, englitazone, AD5075, darglitazone, and rosiglitazone. Fibrates include but are notlimited to gemfibrozil, fenofibrate, clofibrate, or ciprofibrate. Asmentioned previously, a therapeutically effective amount of a fibrate orthiazolidinedione often has toxic side effects. Accordingly, in someembodiments, when a composition described herein is administered incombination with a PPAR agonist, the dosage of the PPAR agonist is belowthat which is accompanied by toxic side effects. In some embodiments,the composition comprises a lyn kinase activator, a TRPM8 agonist, and aPPAR agonist.

The present compositions can also be administered together, orseparately, with a bile-acid-binding resin. Bile-acid-binding resinsinclude but are not limited to cholestyramine and colestipolhydrochloride. In some embodiments, the composition comprises a lynkinase activator, a TRPM8 agonist, and a bile-acid-binding resin.

The present compositions can also be administered together, orseparately, with niacin or nicotinic acid. In some embodiments, thecomposition comprises a lyn kinase activator, a TRPM8 agonist, andniacin or nicotinic acid.

The present compositions can also be administered together, orseparately, with a RXR agonist. RXR agonists include but are not limitedto LG 100268, LGD 1069, 9-cis retinoic acid,2-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-cyclopropyl)-pyridine-5-carboxylicacid, or4-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)2-carbonyl)-benzoicacid. In some embodiments, the composition comprises a lyn kinaseactivator, a TRPM8 agonist, and a RXR agonist.

The present compositions can also be administered together, orseparately, with an anti-obesity drug. Anti-obesity drugs include butare not limited to β-adrenergic receptor agonists, preferably β-3receptor agonists, sibutramine, bupropion, fluoxetine, and phentermine.In some embodiments, the composition comprises a lyn kinase activator, aTRPM8 agonist, and an anti-obesity drug.

The present compositions can also be administered together, orseparately, with a hormone. Hormones include but are not limited tothyroid hormone, estrogen and insulin. Suitable insulins include but arenot limited to injectable insulin, transdermal insulin, inhaled insulin,or any combination thereof. As an alternative to insulin, an insulinderivative, secretagogue, sensitizer or mimetic may be used. Insulinsecretagogues include but are not limited to forskolin, dibutryl cAMP orisobutylmethylxanthine (IBMX). In some embodiments, the compositioncomprises a lyn kinase activator, a TRPM8 agonist, and a hormone.

The present compositions can also be administered together, orseparately, with a tyrophostine or an analog thereof. Tyrophostinesinclude but are not limited to tryophostine 51. In some embodiments, thecomposition comprises a lyn kinase activator, a TRPM8 agonist, andtyrophostine or an analog thereof.

The present compositions can also be administered together, orseparately, with sulfonylurea-based drugs. Sulfonylurea-based drugsinclude, but are not limited to, glisoxepid, glyburide, acetohexamide,chlorpropamide, glibornuride, tolbutamide, tolazamide, glipizide,gliclazide, gliquidone, glyhexamide, phenbutamide, and tolcyclamide. Insome embodiments, the composition comprises a lyn kinase activator, aTRPM8 agonist, and a sulfonylurea-based drug.

The present compositions can also be administered together, orseparately, with a biguanide. Biguanides include but are not limited tometformin, phenformin and buformin. In some embodiments, the compositioncomprises a lyn kinase activator, a TRPM8 agonist, and a biguanide.

The present compositions can also be administered together, orseparately, with an α-glucosidase inhibitor. α-glucosidase inhibitorsinclude but are not limited to acarbose and miglitol. In someembodiments, the composition comprises a lyn kinase activator, a TRPM8agonist, and an α-glucosidase inhibitor.

The present compositions can also be administered together, orseparately, with an apo A-I agonist. In some embodiments, the apo A-Iagonist is the Milano form of apo A-I (apo A-IM). In some embodiments,the apo A-IM is produced by the method of U.S. Pat. No. 5,721,114. Insome embodiments, the apo A-I agonist is a peptide agonist. In someembodiments, the apo A-I peptide agonist is a peptide of U.S. Pat. Nos.6,004,925 or 6,037,323. The present compositions can also beadministered together with apolipoprotein E (apo E). In someembodiments, the apoE is produced by the method of U.S. Pat. No.5,834,596. In some embodiments, the present compositions can beadministered together with an HDL-raising drug; an HDL enhancer; or aregulator of the apolipoprotein A-I, apolipoprotein A-IV and/orapolipoprotein genes. In some embodiments, the composition comprises alyn kinase activator, a TRPM8 agonist, and an apo A-I agonist.

The present compositions can be administered together, or separately,with a known cardiovascular drug. Cardiovascular drugs include but arenot limited to peripheral anti-adrenergic drugs, centrally actingantihypertensive drugs (e.g., methyldopa, methyldopa HCl),antihypertensive direct vasodilators (e.g., diazoxide, hydralazine HCl),drugs affecting renin-angiotensin system, peripheral vasodilators,phentolamine, antianginal drugs, cardiac glycosides, inodilators (e.g.,amrinone, milrinone, enoximone, fenoximone, imazodan, sulmazole),antidysrhythmic drugs, calcium entry blockers, ranitine, bosentan, andrezulin. In some embodiments, the composition comprises a lyn kinaseactivator, a TRPM8 agonist, and a cardiovascular drug.

The present compositions can also comprise, and be administeredtogether, or separately, with a GLP-1 agonist such as, for example,liraglutide (VICTOZA®, SAXENDA®), exenatide (BYETTA®, BYDUREON®),lixisenatide (LYXUMIA®), albiglutide (TANZEUM®), dulaglutide(TRULICITY®), and semaglutide (OZEMPIC®). In some embodiments, thecomposition comprises a lyn kinase activator, a TRPM8 agonist, and aGLP-1 agonist.

The present compositions can also comprise, and be administeredtogether, or separately, with a PPARα/δ dual agonist such as, forexample, Elafibranor. In some embodiments, the composition comprises alyn kinase activator, a TRPM8 agonist, and a PPARα/δ dual agonist.

The present compositions can also comprise, and be administeredtogether, or separately, with an ACC inhibitor such as, for example,GS-0976. In some embodiments, the composition comprises a lyn kinaseactivator, a TRPM8 agonist, and an ACC inhibitor.

The present compositions can also comprise, and be administeredtogether, or separately, with a growth factor such as, for example,Pegylated FGF21. In some embodiments, the composition comprises a lynkinase activator, a TRPM8 agonist, and a growth factor.

The present compositions can also comprise, and be administeredtogether, or separately, with a CCR2/5 blocker such as, for example,Ceniciviroc (CVC). In some embodiments, the composition comprises a lynkinase activator, a TRPM8 agonist, and a CCR2/5 blocker.

The present compositions can also comprise, and be administered together(e.g., within the same composition), or separately, with any one or moreof the following: hexadecanoic acid, linoleic acid, phloretin, VitaminD3, docosanoic acid, quercetin, D-erythro-sphingosine, ricinoleic acid,dodecanoic acid, gossypol, ellagic acid, damnacanthal, heptadecanoicacid, gamma-linolenic acid eicosanoic acid, arachidonic acid,pentacosanoic acid, hexacosanoic acid, dequalinium chloride,tetradecanoic acid, hispidin, tetracosanoic acid, tridecanoic acid,DL-3,4-dihydroxymandelic acid, pentadecanoic acid, ETYA, MNS,palmitoyl-DL-carnitine, adrenic acid, thiazolidinedione, heneicosanoicacid, tricosanoic acid, chelerythrine chloride, aminoindole,docosahexaenoic acid, 5-amino-2-methylindole, cobalt chloride (CoCl₂),piceatannol, eicosapentaenoic acid, sodium nitride (Na₃N), radicicol,safingol, myricitrin, 13-HODE, calcifediol, mead acid, 5-iodotubercidin,sphingosine-1-phosphate, docosadienoic acid, heptadecenoic acid,geldanamycin, calcitriol, eicosadienoic acid, melittin,4-hydroxy-tamoxifen, hydroxyeicosatetraenoic acid, herbimycin A,ET-18-OCH₃, 15-HETE, 5-HETE, eicosatrienoic acid, bryostatin 1,ilmofosine, H-9, H-8, K-252c, HA-1004, K-252a, K-252b, HA-1077, 9-HODE,MDL-27032, UCN-01, bisindolylmaleimide V, calphostin C,7-oxostaurosporine, bisindolylmaleimide VIII, lavendustin A, lavendustinC, KRIBB3, bisindolylmaleimide X, bisindolylmaleimide I, NGIC-I, Go6976, bisindolylmaleimide III, bisindolylmaleimide II,bisindolylmaleimide VI, bisindolylmaleimide VII, dihydrochloride, Pp60c-src, Ro-32-0432, Go 7874, fingolimod, enzastaurin, PP1, PP2, HA-100dihydrochloride, PD 166285, PP1, 1-NM-PP1, CGP77675, PD 180970,dasatinib, PD173952, SU 6656, A-419259, saracatinib, bosutinib,sotrastaurin, KX1-004, CID 755673, ZM 306416, AZM 475271, WH-4-023, TC-S7003, dasatinib monohydrate, TG 100572, A-770041, KX2-391, NVP-BHG712,ER 27319 maleate, TCS 21311, KB SRC 4, and PKC 20-28.

The present compositions can be administered together, or separately,with treatment with irradiation or one or more chemotherapeutic agents.For irradiation treatment, the irradiation can be gamma rays or X-rays.Useful chemotherapeutic agents include, but are not limited to,methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea,cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin,carboplatin, mitomycin, dacarbazine, procarbizine, etoposides,campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin,dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine,vincristine, vinorelbine, paclitaxel, and docetaxel. In someembodiments, a composition described herein further comprises one ormore chemotherapeutic agents and/or is administered concurrently withradiation therapy. In some embodiments, chemotherapy or radiationtherapy is administered prior or subsequent to administration of apresent composition, at least an hour, five hours, 12 hours, a day, aweek, a month, or several months (e.g., up to three months), subsequentto administration of a composition described herein.

The present disclosure also provides methods of reducing blood glucoselevels, weight gain, or fat depot levels in a mammal in need thereof,comprising administering to the mammal an effective amount of any one ormore of the compositions described herein, or comprising administering alyn kinase activator and a TRPM8 agonist in separate administrations.Any combination of lyn kinase activator and a TRPM8 agonist can be usedin the present methods.

The present disclosure also provides methods of treating metabolicsyndrome, Syndrome X, obesity, prediabetes, type II diabetes, type Idiabetes in a mammal in need thereof, comprising administering to themammal an effective amount of any one or more of the compositionsdescribed herein, or comprising administering a lyn kinase activator anda TRPM8 agonist in separate administrations. Any combination of lynkinase activator and a TRPM8 agonist can be used in the present methods.

The present disclosure also provides methods of treatinghypercholesterolemia, hypertension, coronary heart disease, diabeticneuropathy, lipodystrophy, diabetic retinopathy, erectile dysfunction,kidney disease, dyslipidemia, dyslipoproteinemia, a peroxisomeproliferator activated receptor-associated disorder, septicemia, athrombotic disorder, or pancreatitis in a mammal in need thereof,comprising administering to the mammal an effective amount of any one ormore of the compositions described herein, or comprising administering alyn kinase activator and a TRPM8 agonist in separate administrations.Any combination of lyn kinase activator and a TRPM8 agonist can be usedin the present methods.

The present disclosure also provides methods of inducing the beiging ofadipocytes in a mammal in need thereof, comprising administering to themammal an effective amount of any one or more of the compositionsdescribed herein, or comprising administering a lyn kinase activator anda TRPM8 agonist in separate administrations. Any combination of lynkinase activator and a TRPM8 agonist can be used in the present methods.

The present disclosure also provides methods of preventing pancreaticbeta cell degeneration in a mammal in need thereof, comprisingadministering to the mammal an effective amount of any one or more ofthe compositions described herein, or comprising administering a lynkinase activator and a TRPM8 agonist in separate administrations. Anycombination of lyn kinase activator and a TRPM8 agonist can be used inthe present methods.

The present compositions can be administered orally. The compositionscan also be administered by any other convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa,etc.) and can be administered together with another biologically activeagent. Administration can be systemic or local. Various delivery systemsare known, e.g., encapsulation in liposomes, microparticles,microcapsules, capsules, etc., and can be used to administer thecompositions. In some embodiments, more than one composition isadministered to a patient. Methods of administration include, but arenot limited to intradermal, intramuscular, intraperitoneal, intravenous,subcutaneous, intranasal, epidural, oral, sublingual, intranasal,intracerebral, intravaginal, transdermal, rectally, by inhalation, ortopically, particularly to the ears, nose, eyes, or skin. The desiredmode of administration is left to the discretion of the practitioner,and will depend in-part upon the site of the medical condition.

In some embodiments, it may be desirable to administer one or morecompositions locally to the area in need of treatment. This may beachieved, for example, and not by way of limitation, by local infusionduring surgery, topical application, e.g., in conjunction with a wounddressing after surgery, by injection, by means of a catheter, by meansof a suppository, or by means of an implant, said implant being of aporous, non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers. In some embodiments, administration canbe by direct injection at the site (or former site) of anatherosclerotic plaque tissue.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. In someembodiments, the compositions can be formulated as a suppository, withtraditional binders and vehicles such as triglycerides.

The present disclosure also provides compositions described herein foruse in reducing blood glucose levels, weight gain, or fat depot levelsin a mammal in need thereof, comprising administering to the mammal aneffective amount of any one or more of the compositions describedherein.

The present disclosure also provides compositions described herein foruse in treating metabolic syndrome, Syndrome X, obesity, prediabetes,type II diabetes, type I diabetes in a mammal in need thereof,comprising administering to the mammal an effective amount of any one ormore of the compositions described herein.

The present disclosure also provides compositions described herein foruse in treating hypercholesterolemia, hypertension, coronary heartdisease, diabetic neuropathy, lipodystrophy, diabetic retinopathy,erectile dysfunction, kidney disease, dyslipidemia, dyslipoproteinemia,a peroxisome proliferator activated receptor-associated disorder,septicemia, a thrombotic disorder, or pancreatitis in a mammal in needthereof, comprising administering to the mammal an effective amount ofany one or more of the compositions described herein.

The present disclosure also provides compositions described herein foruse in inducing the beiging of adipocytes in a mammal in need thereof,comprising administering to the mammal an effective amount of any one ormore of the compositions described herein. In some embodiments, a lynkinase activator, such as Compound 102, can be used without a TRPM8agonist to induce beiging of adipocytes in a mammal in need thereof.

The present disclosure also provides compositions described herein foruse in preventing pancreatic beta cell degeneration in a mammal in needthereof, comprising administering to the mammal an effective amount ofany one or more of the compositions described herein.

The present disclosure also provides lyn kinase activators and TRPM8agonist for use in reducing blood glucose levels, weight gain, or fatdepot levels in a mammal in need thereof, comprising administering tothe mammal an effective amount of any one or more of the compositionsdescribed herein.

The present disclosure also provides lyn kinase activators and TRPM8agonist for use in treating metabolic syndrome, Syndrome X, obesity,prediabetes, type II diabetes, type I diabetes in a mammal in needthereof, comprising administering to the mammal an effective amount ofany one or more of the compositions described herein.

The present disclosure also provides lyn kinase activators and TRPM8agonist for use in treating hypercholesterolemia, hypertension, coronaryheart disease, diabetic neuropathy, lipodystrophy, diabetic retinopathy,erectile dysfunction, kidney disease, dyslipidemia, dyslipoproteinemia,a peroxisome proliferator activated receptor-associated disorder,septicemia, a thrombotic disorder, or pancreatitis in a mammal in needthereof, comprising administering to the mammal an effective amount ofany one or more of the compositions described herein.

The present disclosure also provides lyn kinase activators and TRPM8agonist for use in inducing the beiging of adipocytes in a mammal inneed thereof, comprising administering to the mammal an effective amountof any one or more of the compositions described herein. In someembodiments, a lyn kinase activator, such as Compound 102, can be usedwithout a TRPM8 agonist to induce beiging of adipocytes in a mammal inneed thereof.

The present disclosure also provides lyn kinase activators and TRPM8agonist for use in preventing pancreatic beta cell degeneration in amammal in need thereof, comprising administering to the mammal aneffective amount of any one or more of the compositions describedherein.

The present disclosure also provides compositions described herein foruse in preparation of a medicament for reducing blood glucose levels,weight gain, or fat depot levels in a mammal in need thereof, comprisingadministering to the mammal an effective amount of any one or more ofthe compositions described herein.

The present disclosure also provides compositions described herein foruse in preparation of a medicament for treating metabolic syndrome,Syndrome X, obesity, prediabetes, type II diabetes, type I diabetes in amammal in need thereof, comprising administering to the mammal aneffective amount of any one or more of the compositions describedherein.

The present disclosure also provides compositions described herein foruse in preparation of a medicament for treating hypercholesterolemia,hypertension, coronary heart disease, diabetic neuropathy,lipodystrophy, diabetic retinopathy, erectile dysfunction, kidneydisease, dyslipidemia, dyslipoproteinemia, a peroxisome proliferatoractivated receptor-associated disorder, septicemia, a thromboticdisorder, or pancreatitis in a mammal in need thereof, comprisingadministering to the mammal an effective amount of any one or more ofthe compositions described herein.

The present disclosure also provides compositions described herein foruse in preparation of a medicament for inducing the beiging ofadipocytes in a mammal in need thereof, comprising administering to themammal an effective amount of any one or more of the compositionsdescribed herein.

The present disclosure also provides compositions described herein foruse in preparation of a medicament for preventing pancreatic beta celldegeneration in a mammal in need thereof, comprising administering tothe mammal an effective amount of any one or more of the compositionsdescribed herein.

In order that the subject matter disclosed herein may be moreefficiently understood, examples are provided below. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting the claimed subject matter in anymanner. Throughout these examples, molecular cloning reactions, andother standard recombinant DNA techniques, were carried out according tomethods described in Maniatis et al., Molecular Cloning—A LaboratoryManual, 2nd ed., Cold Spring Harbor Press (1989), using commerciallyavailable reagents, except where otherwise noted.

EXAMPLES Example 1: Progressive Reduction in Fasting Glucose

This Phase 2a clinical trial was conducted in the U.S. (103 subjects)and Korea (27 subjects). Subjects were 18-75 years of age, possessedBMIs of 20-40 kg/m², possessed glycosylated HbA1c of 7-10%, were eithermetformin-naive or washed off of metformin, and were not exposed toother anti-diabetic agents within the previous 6 months. Subjects weretreated with one of four active doses (100 mg once-daily (qd), 100 mgtwice-daily (bid), 200 mg qd, or 200 mg bid) of Compound 102 or placebofor 4 weeks after having 3 weeks of placebo run-in. FIG. 1 shows theprogressive reduction in fasting plasma glucose (FPG). Body weights, assecondary endpoints, were measured at Day 1 and Day 29 and at thefollow-up visit 1 week after treatment stopped, at Day 35. This studyrevealed statistically significant improvements in body weight loss overthe 4-week treatment period. In general, all treatment groups exhibitedsome degree of weight loss at Day 29 even when they were notsignificant. Also, all groups except for the 200 mg bid group showedcontinued loss 1 week after treatment (Day 35) compared to Day 29 (see,FIG. 2). The effect was most pronounced in the U.S. subjects and in the100 qd dose group.

The fact that weight loss continued for at least 1 week after treatmentwas terminated, at a time when drug has long since left the body, isconsistent with a mechanism whereby Compound 102 transforms whiteadipose tissue to “beige” adipose tissue, which is able to burn energyand effect weight loss. The transformed state of tissue type would beexpected to last longer than the presence of the drug.

Example 2: Compound 102 Induces Beige Adipocyte Gene Expression

Human adipocyte precursor cells isolated from subcutaneous abdominal fatwere purchased from LaCell, LLC, New Orleans, La. Cells were seeded andgrown to confluence in DMEM/F12 with 10% heat inactivated FBS.Differentiation to mature adipocytes was induced in medium composed of70% DMEM and 30% DMEMF12 supplemented with 3% FBS, 1 μM dexamethasone(Sigma D4902), 33 NM biotin (Sigma B4639), 100 nM insulin (Sigma 15500),20 μM pantothenate (Sigma P5155), 5 μM rosiglitazone (AK ScientificF325) and 500 NM IBMX (Sigma 15879) for four days. Cells were maintainedin medium composed of 70% DMEM and 30% DMEMF12 supplemented with 3% FBS,1 μM dexamethasone, 33 μM biotin, 100 nM insulin, and 20 NM pantothenatefor seven days before experimental treatment.

A solution of 10 mM Compound 102 was prepared in DMSO and diluted to 60μM or 30 μM in maintenance medium without dexamethasone for celltreatment. In some experiments, cells were treated with 20 μM menthol(Sigma M2772).

Total RNA was isolated from adipocyte cultures grown in 12-well platesusing Trizol and Qiagen RNAeasy kits. Reverse transcriptase and PCR wereconducted in one reaction with the reverse PCR primer priming cDNAsynthesis using SuperScript® III Platinum® One-Step Quantitative RT-PCRSystem with Rox from Invitrogen (11745). Predesigned Taqman primer-probesets were purchased from Applied Biosystems for the following humantranscript sequences: UCP1 (Hs249211), PPARGC1α (HS527078), PPARU(Hs103110), CPT1b (Hs439777), and GLUT4/SLC2A4 (Hs380691). Aplicons weredesigned to span an intron-exon junction to avoid amplification ofgenomic sequences. Each sample RT-PCR assay was conducted in duplicate.

As depicted in FIG. 3, human adipocytes treated with Compound 102experienced significant increases, at day 4, in the expression ofseveral genes associated with the beiging of white adipose tissue: 1)UCP-1, which triggers mitochondrial fat oxidation and is associated withthe differentiation of white adipocytes into beige adipocytes; 2) GLUT4,which increases glucose utilization and can be seen as a result of“beiging”; 3) Carnitine palmitoyltransferase-Ib (CPT-1b), which isinduced during “beiging” and involved in the oxidization of fat inmitochondria; 4) Adipose Triglyceride Lipase (ATGL), the rate limitingenzyme for lipolysis; and 5) Transient Potential Melastatin 8 Receptor(TRPM8R).

As depicted in FIG. 4, markers of beige adipose tissue GLUT4 rRNA andUCP1 mRNA continued to increase over the 7-day treatment period inprimary cultured human adipocytes.

As depicted in FIG. 5, expression of GLUT4 protein continued to existover the 7-day treatment period in primary cultured human adipocytes.

As depicted in FIG. 6, expression of UCP1 protein continued to existover the 7-day treatment period in primary cultured human adipocytes.

As depicted in FIG. 7, Compound 102 induced the expression of the UCP1activators PPARα and PGC-1β.

As depicted in FIG. 8, Compound 102 induced the expression of TRPM8menthol receptor mRNA.

Compound 102 is an activator of the IRS 1/PI3 kinase pathway (PI3K).PI3K produces PIP2, a membrane phospholipid that is required foractivity of the TRPM8 receptor. The following inhibitors were used todetermine their effect on lowering Compound 102-induced UCP1 expressionover 4 days: 1) a specific PI3K inhibitor, LY294002 (20 NM), 2) a PKAinhibitor, H89 (20 μM), and 3) a TRPM8R inhibitor, PBMC (20 nM). Allthree inhibitors reduced UCP1 mRNA to levels of unstimulated controls orlower (see, FIG. 9). These results indicate that PI3K activity, PKAactivity, and TRPM8 receptor activity are required for UCP1 expressionafter treatment with Compound 102.

Increased levels of UCP-1 adipose tissue protein was observed in db/dbmice treated for 3 weeks with Compound 102 (100 mg/kg qd). Adiposetissue was collected 4 hours after the last dose of Compound 102.Densitometry quantitation from 4 separate experiments was performed toobtain the values shown in FIG. 10 (panel a). A representative Westernblot from 4 separate experiments conducted is shown in FIG. 10 (panelb). In agreement with the increased levels of UCP-1 mRNA and proteinobserved in primary human adipocytes, increased levels of UCP-1 proteinin mice treated with Compound 102 was also observed.

As depicted in FIG. 11, a TRPM8 inhibitor blocked Compound 102-inductionof UCP-1, demonstrating that lyn kinase activation induces UCP-1 via theaction of TRPM8.

The ability of menthol and Compound 102 to induce UCP1 in adipocytes wasalso examined. Treatment with 30 μM menthol (serum C_(max)) and 30 NMCompound 102 together synergitically elevated UCP1 expression overlevels stimulated by Compound 102 alone in a 7 day treatment (see, FIG.12, panel a). Menthol alone did not induce expression. A similarincrease was observed in GLUT4 expression when menthol was added toCompound 102 (see, FIG. 12, panel b). Menthol doubles the induction ofUCP1 and GLUT4 by Compound 102.

As depicted in FIG. 13, menthol by itself does effect insulinsensitization or glycemic control in a rodent oral glucose tolerancetest. In contrast, menthol potentiates the the insulin sensitizingaction of Compound 102 in a rodent oral glucose tolerance test.

Various modifications of the described subject matter, in addition tothose described herein, will be apparent to those skilled in the artfrom the foregoing description. Such modifications are also intended tofall within the scope of the appended claims. Each reference (including,but not limited to, journal articles, U.S. and non-U.S. patents, patentapplication publications, international patent application publications,gene bank accession numbers, and the like) cited in the presentapplication is incorporated herein by reference in its entirety.

What is claimed is:
 1. A composition comprising: a lyn kinase activator,or a pharmaceutically acceptable salt thereof; and a TRPM8 agonist;wherein the lyn kinase activator is of the formula:

 or a pharmaceutically acceptable salt thereof, and the TRPM8 agonist ismenthol.
 2. A method of treating obesity, prediabetes, type II diabetes,type I diabetes, or dyslipidemia, in a mammal in need thereof,comprising administering to the mammal an effective amount of a lynkinase activator having the formula:

or a pharmaceutically acceptable salt thereof, and menthol.
 3. Themethod of claim 2, wherein the lyn kinase activator and menthol arepresent in the same composition.
 4. A method of inducing the beiging ofadipocytes in a mammal in need thereof, comprising administering to themammal an effective amount of a lyn kinase activator having the formula:

or a pharmaceutically acceptable salt thereof, and menthol.
 5. Themethod of claim 4, wherein the lyn kinase activator and menthol arepresent in the same composition.